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ZNF593 regulates the cGAS-mediated innate immune response by attenuating cGAS-DNA binding

Cell Death & Differentiation volume 32, pages 1845–1858 (2025)Cite this article

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Abstract

The enzyme cyclic GMP-AMP synthase (cGAS) is essential for detecting aberrantly located double-stranded DNA (dsDNA) from genomic, mitochondrial, and microbial origins. Through the synthesis of 2′3′-cGAMP, cGAS triggers the activation of the stimulator of interferon genes pathway, which initiates in vivo innate immune responses. Here, we identify zinc finger proteins ZNF593, which translocate from the nucleus to the cytoplasm after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production. ZNF593 directly binds to cGAS and suppresses its activation by inhibiting the cGAS-dsDNA interaction. ZNF593 deficiency increases IRF3 nuclear translocation and promotes DNA virus-triggered IFN production. Furthermore, ZNF593 deficiency promotes antiviral innate responses in vivo, improving survival rates in mice against HSV-1 infection. We further find that ZNF593 plays a protective role in systemic lupus erythematosus (SLE) pathology. Notably, replenishing ZNF593 effectively reduced IFN production in peripheral blood mononuclear cells (PBMCs) of SLE patients or in the TMPD-induced murine SLE model. Our findings suggest that ZNF593 negatively regulates IFN-β signaling by targeting cGAS activation, providing new insights into the regulatory mechanisms for antiviral defenses and autoimmune diseases.

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Fig. 1: cGAS interacted with ZNF593.
Fig. 2: ZNF593 negatively regulates IFN-β signaling.
Fig. 3: ZNF593 deficiency impairs virus replication.
Fig. 4: ZNF593 negatively regulates dsDNA-triggered phosphorylation of TBK1 and IRF3.
Fig. 5: ZNF593 deficiency protect mice from HSV-1 infection.
Fig. 6: ZNF593 inhibits the DNA-binding affinity of cGAS.
Fig. 7: ZNF593 is associated with the pathology of SLE.

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Data availability

All relevant data that support the study are provided in the article and Supplementary Information. Other relevant data can be obtained from the corresponding author upon reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank Dr. Deyu Zhu (Shandong University, China) for kindly providing Human cGAS purified protein. This work was supported by the grants from the National key research and development program (2024YFA0918401 to BL), the National Natural Science Foundation of China (82222027, 32270918 to BL, 82301984 to XB, 82321002, 32230033, 81930039 to CG), grants from the National key research and development program (2021YFC2300603 to CG), grants from Natural Science Foundation of Shandong Province (ZR201911140289 to CG), the China Postdoctoral Science Foundation (2024M751821 to XB), and Shandong Postdoctora1 Science Foundation (SDCX-ZG-202400006 to XB).

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Authors and Affiliations

  1. Key Laboratory of Infection, Immunity and prevention of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, PR China

    Xuemei Bai, Na Dong, Nan Cao, Min Zhou, Jiahua Yuan, Yuling Zhang, Yaxing Liu, JiaJia Zhang, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Chengjiang Gao & Bingyu Liu

  2. Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China

    Xuemei Bai, Na Dong, Nan Cao, Min Zhou, Jiahua Yuan, Yuling Zhang, Yaxing Liu, JiaJia Zhang, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Chengjiang Gao & Bingyu Liu

  3. Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China

    Tian Chen

  4. Department of Rheumatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, PR China

    Qiang Shu

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  1. Xuemei Bai
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Contributions

CG and BL conceived the study; CG and BL designed and supervised the research; XB performed the research; ND, NC, MZ, JY, YZ, YL, JZ contributed reagents and experimental advice; TC, FL, WS, YZ, WZ, QS provided discussions; CG, BL and XB analyzed the data and wrote the paper.

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Correspondence to Chengjiang Gao or Bingyu Liu.

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Bai, X., Dong, N., Cao, N. et al. ZNF593 regulates the cGAS-mediated innate immune response by attenuating cGAS-DNA binding. Cell Death Differ 32, 1845–1858 (2025). https://doi.org/10.1038/s41418-025-01508-5

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